Mechanisms of Enzyme-Catalyzed Reduction of Two Carcinogenic Nitro-Aromatics, 3-Nitrobenzanthrone and Aristolochic Acid I: Experimental and Theoretical Approaches

International Journal of Molecular Sciences

Marie Stiborová⁴  Eva Frei¹  Heinz H. Schmeiser²  Volker M. Arlt³ 

[1] Division of Preventive Oncology, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; E-Mail:;Radiopharmaceutical Chemistry E030, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; E-Mail:;Analytical and Environmental Sciences Division, MRC-PHE Centre for Environmental & Health, King’s College London, 150 Stamford Street, London SE1 9NH, UK; E-Mail:;Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030, CZ-12843, Prague 2, Czech Republic; E-Mail:

关键词: nitro-aromatics;    3-nitrobenzanthrone;    aristolochic acid I;    DNA adducts;    molecular modeling;    NAD(P)H:quinone oxidoreductase;    cytochrome P450;   

DOI  :  10.3390/ijms150610271

来源: mdpi

【 摘 要 】

This review summarizes the results found in studies investigating the enzymatic activation of two genotoxic nitro-aromatics, an environmental pollutant and carcinogen 3-nitrobenzanthrone (3-NBA) and a natural plant nephrotoxin and carcinogen aristolochic acid I (AAI), to reactive species forming covalent DNA adducts. Experimental and theoretical approaches determined the reasons why human NAD(P)H:quinone oxidoreductase (NQO1) and cytochromes P450 (CYP) 1A1 and 1A2 have the potential to reductively activate both nitro-aromatics. The results also contributed to the elucidation of the molecular mechanisms of these reactions. The contribution of conjugation enzymes such as N,O-acetyltransferases (NATs) and sulfotransferases (SULTs) to the activation of 3-NBA and AAI was also examined. The results indicated differences in the abilities of 3-NBA and AAI metabolites to be further activated by these conjugation enzymes. The formation of DNA adducts generated by both carcinogens during their reductive activation by the NOQ1 and CYP1A1/2 enzymes was investigated with pure enzymes, enzymes present in subcellular cytosolic and microsomal fractions, selective inhibitors, and animal models (including knock-out and humanized animals). For the theoretical approaches, flexible in silico docking methods as well as ab initio calculations were employed. The results summarized in this review demonstrate that a combination of experimental and theoretical approaches is a useful tool to study the enzyme-mediated reaction mechanisms of 3-NBA and AAI reduction.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.